This is a K23 award application for Dr. Zachary A. Miller, a behavioral neurologist at the University of California, San Francisco Memory and Aging Center (MAC) who is establishing himself as a young investigator in patient-oriented clinical research focusing on language processing in neurodegenerative disease. This K23 award will provide Dr. Miller with the necessary support to accomplish the following: (1) gain expertise in neurodegenerative disease and the cognitive neuroscience of language processing; (2) develop proficiency in the use and analysis of structural and functional neuroimaging; (3) gain experience in evaluating neurodevelopmental and genetic factors in neurodegenerative patients; (4) advance his knowledge of biostatistics; (5) gain exposure and training in the neuropathology of language disorders; and (6) develop an independent clinical research career. To achieve these goals, he assembled a multidisciplinary mentoring team with two primary mentors: Dr. Maria Luisa Gorno-Tempini (a neurologist with expertise in language disorders and advanced neuroimaging techniques) and Dr. Bruce Miller (a neurologist with expertise in behavior, neurodegenerative disease, and clinical research); a co-mentor: Dr. Srikantan Nagarajan (a bioengineer with expertise in magnetoencephalography); and three advisors: Dr. Matt State (a psychiatrist with expertise in neurodevelopmental disorders and genetics), Dr. William Seeley (a neurologist with expertise in neuropathology and functional imaging), and Dr. John Neuhaus (a biostatistician with expertise in multivariate analyses). The proposed research investigates the effect of pre-morbid, individual characteristics related to language disabilities and clinical presentation in neurodegenerative diseases. The central hypothesis is that neurodevelopmental factors are associated with increased vulnerability of the language networks to disease, leading to specific language presentations, imaging changes, and disease progression. We will study PPA and FTD gene carriers to examine the consequences of language learning disability and hand preference on clinical, cognitive, and neuroimaging phenotype. We will collect a standardized neurodevelopmental history, detailed cognitive assessment, and imaging data to determine phenotypic differences between PPA patients with and without a history of language-learning disabilities at presentation (Aim 1). We will establish hand preference and language lateralization patterns using magnetoencephalography in PPA and healthy control subjects and correlate them with measures of structural brain symmetry (Aim 2). We will collect longitudinal cognitive and neuroimaging data on PPA and FTD gene carriers and compare patterns of progression in subjects with and without language learning disabilities (Aim 3). This research will increase understanding of pre-morbid factors on clinical heterogeneity in PPA, direct future studies into early diagnostic and treatment strategies, and offer novel neurodevelopmental and imaging measures as new tools for PPA characterization and diagnosis. This K23 training will enable Dr. Miller to apply concepts of selective neurodevelopmental vulnerability to the understanding of other neurodegenerative diseases.]